Rim HK, Cho W, Sung SH, Lee KT

Nodakenin, a coumarin isolated from the roots of Angelicae gigas, has been reported to possess neuroprotective, anti-aggregatory, anti-bacterial, and memory enhancing effects. In the present study, we investigated the anti-inflammatory effects of nodakenin by examining its in vitro inhibitory effects on inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory ...

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cytokines in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and mouse peritoneal macrophages, and its in vivo effects on LPS-induced septic shock in mice. Our results indicate that nodakenin concentration-dependently inhibits iNOS and COX-2 at the protein, mRNA, and promoter binding levels and that these inhibitions cause attendant decreases in the productions of nitric oxide (NO) and prostaglandin E(2) (PGE(2)). Furthermore, we found that nodakenin inhibits the productions and mRNA expressions of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β induced by LPS. Molecular data revealed that nodakenin suppressed the transcriptional activity and translocation of nuclear factor-kappa B (NF-κB) by inhibiting inhibitory kappa B-α (IκB-α) degradation and IκB kinase-α/β (IKK-α/β) phosphorylation. In addition, nodakenin was found to significantly inhibit the LPS-induced binding of transforming growth factor-β-activated kinase 1 (TAK1) to tumor necrosis factor receptor-associated factor 6 (TRAF6) by reducing TRAF6 ubiquitination. Pretreatment with nodakenin reduced the serum levels of NO, PGE(2) and pro-inflammatory cytokines, and increased the survival rate of mice with LPS-induced endotoxemia. Taken together, our data suggest that nodakenin down-regulates the expressions of the pro-inflammatory iNOS, COX-2, TNF-α, IL-6, and IL-1β genes in macrophages through interfering with the activation of TRAF6, and thus, preventing NF-κB activation.

Date: May. 25, 2012

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